The proposed research project is centered around the mechanisms involved in regulation of Trypanosoma cruzi growth in mammalian host cells, with special emphasis on the role of growth factors. T. cruzi is a hemo- flagellate which causes the fatal Chagas's disease, which is most prevalent in South American countries, affecting millions of people by causing heart disease and eventual death by cardiac arrest. Dr. Lima's investigation of the mechanism of T. cruzi growth is critical since there is no treatment or cure for this disease. T. cruzi proliferate intracellularly, thus it is likely that athe parasite is influenced by the same factors that regulate cell growth and differentiation. Recent investigations show that growth of T. cruzi is stimulated by epidermal growth factor (EGF) and other members of this ligand family such as transforming growth factor alpha (TGF-a) and heparin-binding epidermal growth factor (IIB-EGF). Dr. Lima's lab has demonstrated that T. cruzi amastigotes, the intracellular form of the parasite, have an EGF receptor. The receptor has intrinsic tyrosine kinase activity which is stimulated by addition of EGF, TGF-alpha and HB-EGF. Analysis of HB-EGF and TGF-a stimulated amastigotes show that phosphorylation of relevant proteins in the cell lysate was significantly higher in TGF-a stimulated lysates that either EGF or HB-EGF. This suggests that TGF-a may play a significant role in T. cruzi growth and pathogenesis by inducing amastigote growth and signal transduction events. My specific aims in this proposal are to investigate (1) whether binding of EGF to amastigotes is completed by TGF-alpha and HB-EGF (2) the affinity constant of these growth factors to the amastigote EGF receptor (3) the biological relevance of TGF-alpha stimulation of amastigote growth by using transgenic mice deficient in TGF-alpha (40 the effect of TGF-alpha on signal transduction pathways in T. cruzi amastigotes.